{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:30:00Z","timestamp":1787765400816,"version":"build-2784847793"},"reference-count":34,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2017,9,4]],"date-time":"2017-09-04T00:00:00Z","timestamp":1504483200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["MDA186435"],"award-info":[{"award-number":["MDA186435"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007306","name":"Arizona Department of Health Services","doi-asserted-by":"publisher","award":["ADHS16-110501"],"award-info":[{"award-number":["ADHS16-110501"]}],"id":[{"id":"10.13039\/100007306","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Translational Genomics Research Institute Bridge Funding"},{"name":"Helios Foundation"},{"name":"Freeport-McMoRan Copper and Gold Foundation"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 (\n                    <ns4:italic>UBA1<\/ns4:italic>\n                    ). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the\n                    <ns4:italic>UBA1<\/ns4:italic>\n                    gene, which contains the active adenylation domain (AAD).\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    In this study, our group characterized the three known missense variants\n                    <ns4:italic>in vitro<\/ns4:italic>\n                    . Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions\n                    <ns4:italic>in vitro<\/ns4:italic>\n                    to determine possible biochemical effects of the missense variants.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1\u2019s enzymatic activity with Ubiquitin, to other roles such as altering\n                    <ns4:italic>UBA1<\/ns4:italic>\n                    \u00a0mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important\n                    <ns4:italic>in vivo<\/ns4:italic>\n                    binding partners.\u00a0 These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations\u2019 biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.\n                  <\/ns4:p>","DOI":"10.12688\/f1000research.11878.1","type":"journal-article","created":{"date-parts":[[2017,9,4]],"date-time":"2017-09-04T09:30:18Z","timestamp":1504517418000},"page":"1636","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy"],"prefix":"10.12688","volume":"6","author":[{"given":"Chris D.","family":"Balak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse M.","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.12835.r25643, Barrington Burnett, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD, USA, 19 Sep 2017, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/6-1636\/v1#referee-response-25643","order":0,"name":"referee-response-25643","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.12835.r25639, Christine Beattie, Department of Neuroscience, \u00a0The Ohio State University, Columbus, OH, USA, 25 Sep 2017, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/6-1636\/v1#referee-response-25639","order":1,"name":"referee-response-25639","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This study was funded by a research grant (MDA186435) from the Muscular Dystrophy Association of America, Arizona Department of Health Services Arizona Biomedical Research Commission (ADHS16-110501), and the Translational Genomics Research Institute Bridge Funding. CDB was supported, in part, by a fellowship from Freeport-McMoRan Copper and Gold Foundation, and the Helios Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).","order":0,"name":"copyright-info","label":"Copyright"},{"value":"Monte Gates, Heidi R Fuller, Neurobiology of Disease & Regeneration DOI: 10.3410\/f.730937784.793538245","URL":"http:\/\/f1000.com\/prime\/730937784#eval793538245","order":0,"name":"recommendation-793538245","label":"Recommendation","group":{"name":"prime-recommendations","label":"F1000Prime article recommendations"}}]}}